ToxSci Advance Access originally published online on September 16, 2004
Toxicological Sciences 2004 82(2):562-569; doi:10.1093/toxsci/kfh279
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Toxicological Sciences vol. 82 no. 2 © Society of Toxicology 2004; all rights reserved.
c-fos mRNA Expression in Rat Cortical Neurons During Glutamate-Mediated Excitotoxicity
* Bayer HealthCare, Pharma Research Centre, Aprather Weg, 42096 Wuppertal, Germany; and Department of Biochemistry, Trinity College, Dublin 2, Ireland
Received July 8, 2004; accepted September 3, 2004
We have previously reported that exposure of mouse cerebellar granule cells (mCGCs) to excitotoxic concentrations of glutamate (Glu) induced a delayed, elevated, and sustained expression of c-fos mRNA, which was N-methyl-D-aspartic acid (NMDA) receptor mediated. In this study, the overstimulation of Glu receptors in primary rat cortical neurons by excitotoxins was used to study the cellular events triggering excitotoxic neuronal cell death, as the rat is the preferred species in regulatory and nonregulatory toxicological investigations. Exposure of rat cortical neurons to excitotoxins at high, toxic concentrations showed a change in the c-fos mRNA expression profile from a transient expression to one of sustained elevated levels. The excitotoxins induced much higher levels of c-fos mRNA in rat cortical neurons than in the mouse CGC system. Glu-induced c-fos mRNA expression, under excitotoxic conditions, was inhibited by D-2-amino-5-phosphonopentanoate (AP5) but not 6-cyano-7-nitro-quinoxaline-2,3-dione (CNQX), indicating an event mediated by the NMDA subtype of Glu receptors. Using 12 compounds, which covered a range of nontoxic, toxic, and excitotoxic effects on rat cortical neurons, excitotoxicity was paralleled by a sustained, elevated c-fos mRNA expression. Furthermore, on account of the high expression levels of c-fos mRNA under excitotoxic conditions, it is suggested that an unambiguous elevation in c-fos mRNA expression at a single time point of 60 min can be used to predict the excitotoxic properties of a range of functionally different chemical compounds. In view of the high levels of expression of c-fos mRNA, the rat cortical cell system may also be used as a more sensitive model than mCGCs for investigations into early markers of excitotoxicity.
Key Words: excitotoxicity; c-fos; RT-PCR; IEGs; rat cortical neurons.
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